Co-prescription of cytochrome P450 2D6/3A4 inhibitor-substrate pairs in clinical practice. A retrospective analysis of data from Norwegian primary pharmacies

Abstract

Objective: Inhibition of cytochrome P (P450) (CYP) enzymes, in particular CYP3A4 and CYP2D6, is an important drug-interacting mechanism. The objective of our study was to assess how frequently CYP3A4 and CYP2D6 inhibitors are co-prescribed with substrates of the respective enzymes.

Methods: Included inhibitors were clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole and nefazodone (CYP3A4 inhibitors) and bupropion, fluoxetine, paroxetine and terbinafine (CYP2D6 inhibitors). The inhibitors were combined with substrates shown to be pharmacokinetically sensitive towards inhibition (190 drug pairs in total). Lists of patients receiving inhibitors and substrates were drawn from prescription databases (approximately 43,500 patients) of three Norwegian primary pharmacies during a 6-month period (July 2002 to January 2003). The lists were matched on name and date of birth to identify patients using drug pairs. Concurrent use was made probable from dates of purchase and drug profiles.

Results: Inhibitors were prescribed to 2,062 patients. Altogether, 369 events of substrate co-prescription were registered. The highest frequencies of co-prescribed substrates were found for paroxetine (101 events per 267 patients, 38%), fluoxetine (36 events per 110 patients, 33%) and clarithromycin (59 events per 242 patients, 24%). The drugs most often detected in combination with inhibitors were codeine (116 events) and metoprolol (38 events) for CYP2D6 and zopiclone (45 events) and simvastatin (26 events) for CYP3A4.

Conclusion: Several commonly used CYP2D6 and CYP3A4 inhibitors are frequently co-prescribed with substrates in Norwegian clinical practice. Alertness when inhibitors are prescribed would aid physicians and pharmacists to detect many drug combinations with potential interaction risk.